This project studies the various genetically specified mechanisms involved in the pathogenesis of murine leukemia virus (MuLV)-related disease, including those determining sensitivity or resistance of inbred mice to exogenous infection and those related to spontaneous lymphomagenesis. One area of study involves the induction of murine AIDS (MAIDS) lymphoproliferation and immunosuppression following infection of adult mice by the defective BM5def MuLV and replication competent MuLV helper virus. MHC Class I and II genes, notably those of the Class I H2D end, as well as non-MHC-linked loci, mediate infection by the defective virus or helper virus and prevent or modify disease. In crosses of sensitive and resistant strains, disease induction patterns can be attributed only in part to the predictable influences of Fv-1 genotype (a powerful mediator of helper virus infection and spread) and H-2 haplotype. In an effort to obtain clues as to mechanisms of resistance, PCR analyses of backcross and F2 mice for SSLP associations are being used in attempts to chromosomally map resistance loci in crosses of the sensitive/resistant pairs C57BL/6 and 129, B10.RIII and RIIIS, and SWXL-4 and SWR. A second area of emphasis is the study of spontaneous hematopoietic tumorigenesis in NFS v-congenic (NFS.V) mouse strains which carry germ-line integrations of ecotropic MuLV derived from AKR or C58 mice. In contrast to the parental NFS (virus negative and very low tumor incidence), NFS.V mice have a sharply increased lymphoma incidence and, as compared to the parental AKR or C58 (high virus and high thymic T cell lymphoma), both T and B lineage lymphomas occur, about 90% being B cell. In the B lineage group at least 45% of the tumors were found to represent an unusual class of low to high grade marginal zone lymphomas. Over 600 tumors have been classified morphologically and most have been characterized for T or B cell lineage, cell surface antigen phenotype, and clonality as defined by IgH or TCRb rearrangements and new ecotropic MuLV integrations. Successful transplantation has been achieved for 4 B cell tumors and 2 cell lines have been established. The majority of tumors have one or more new somatic viral inserts and studies of host and retroviral molecular interactions leading to lymphomagenesis are in progress.